Traumatic Brain Injury (TBI) is a non-degenerative, non-congenital insult to the brain from an external mechanical force, possibly leading to permanent or temporary impairments of cognitive, physical and psychosocial functions with an associated diminished or altered state of consciousness (Brown, A. W., et. al., 2008, Arch. Phys. Med. Rehabil., 89 (Supp. 1), S3-8). TBI is a major cause of death and disability worldwide. It is estimated that more than 1.5 million Americans sustain a TBI each year, and the incidence of TBI in other industrialized countries is comparable to the U.S. (Traumatic Brain Injury: Methods for Clinical and Forensic Neuropsychiatric Assessment, p. 2, Granacher, ed., CRC Press 2003). For example, in Europe there are approximately 66,000 deaths annually attributed to TBI (Socin, D. M., et al. (1995). JAMA 273(22), 1778-80). Some patients have a long-term or lifelong need for help to perform activities of daily living as a result of TBI.
Despite the enormity of the problem posed by TBI, there are currently no approved medications proven to be effective in improving mortality or in improving outcomes following TBI. However, two recent clinical trials have demonstrated successful treatment of TBI with the steroid hormone progesterone (Xiao et al, 2008, Crit. Care, 12: R61; Wright et al Ann. Emerg. Med. 2007, 49: 391-402). Both studies showed that progesterone is safe and well tolerated in TBI patients, and that administration of progesterone to TBI patients leads to decreased mortality. Furthermore, patent applications WO2006/102644, WO2006102596, and WO2008/039898 outline methods for treatment of TBI by parenterally administering progestogen.
The most effective route of administration of progestogens such as progesterone is via parenteral, or intravenous administration. However, the hydrophobic nature of the progesterone molecule, and hence its poor solubility in water, presents formulation limitations. Aqueous solutions do not offer formulations capable of delivering effective therapeutic doses of progesterone to patients. However, progesterone is sufficiently lipophilic to enable therapeutically effective concentrations to be prepared in hydrophobic solvents, such as triglyceride based solvents.
The delivery of hydrophobic drugs via intravenous infusion of oil-in-water emulsions is known in the art. Examples include Taxol® and Abraxane®, which are nanoformulations of the chemotherapy drug paclitaxel designed for intravenous administration, and Diprivan®, which is a lipid emulsion formulation of the anaesthetic propofol marketed by APP pharmaceuticals, IL, USA. Intravenous administration of progesterone with an oil-in-water emulsion has also been previously described (Wright D W et al. supra; Trotter et al, Journal of Clin. Endocrinol. & Metab. (1999) Vol. 84, page 4531).
The ProTECT study (Wright et al., Ann. Emerg. Med. 2007, 49: 391-402) utilized a 2-component system, wherein progesterone is firstly dissolved in an alcoholic solution (first component), and this alcoholic progesterone solution is subsequently injected into the commercially available lipid emulsion Intralipid® 20% (Fresenius Kabi, Sweden) (second component), and manually mixed (such as by shaking) shortly before intravenous administration of the alcoholic solution/emulsion mixture. There are multiple disadvantages of using this method of preparation:
Firstly, administration of alcoholic solutions to TBI patients is not desirable. Secondly, whilst the presence of alcohol aids solubilisation of the progesterone, low shear manual mixing does not enable all of the progesterone to enter the oil phase. Consequently such emulsions are capable of solubilising only a limited amount of progesterone, and large amounts of lipid must therefore be administered in order to achieve the desired serum-progesterone levels. However, administration of large volumes of emulsion, and/or large amounts of lipid to the patient can have serious consequences, such as induction of hyperlipidemia or oedema. The patient is, as a result, exposed to an undesirable lipid and/or liquid load and is placed at risk of adverse reactions.
Furthermore, non-dissolved progesterone is susceptible to crystallisation, and subsequently oxidation in the aqueous phase, thus causing not only elevated levels of particulate matter to accumulate in the composition, but also high levels of degradation products of the active ingredient. Indeed, it has been shown that, when an alcoholic solution of progesterone is injected into a commercial lipid emulsion composition (such as Intralipid® 20%), a fraction of the hormone is found in crystalline form rather than becoming solubilised in the emulsion. This non-solubilized progesterone has been reported to be adsorbed at the surface of the infusion bags and feed ducts. The observation that not all of the progesterone enters the oil phase of these 2-component emulsions leads to uncertainty as to the concentration of progesterone achieved in the final composition, and the bio-availability of the hormone.
Finally, due to stability issues, the progesterone-lipid mixture of 2-component systems must be prepared only hours ahead of administration (i.e. the first component is added to the second component and mixed within hours of use), as the resulting mixture may not be stored at room temperature. It is both time consuming and inconvenient for medical practitioners to prepare such mixtures on demand, and particularly unsatisfactory in the context of TBI therapy, where prompt treatment can be important to patient outcome.
Alternative methods for making hormone-containing emulsions describe the incorporation of hormone directly into the oil during manufacture of the lipid emulsion.
WO 96/10991 describes pharmaceutical compositions for transmucosal administration of estradiol in combination with a progestin.
WO 01/28555 describes oil-in-water emulsion systems for the delivery of polyfunctional active ingredients. The emulsions comprise, in addition to an active ingredient, polarity modifiers, said to be capable of modifying the interaction between the polyfunctional active ingredient and the oil phase, by serving as a bridge to reduce the effects of the gap in polarity between the active ingredient and the oil.
US 2007/0071777 describes a method of making a 20% lipid emulsion comprising progesterone, which serves as a stock solution that is used to prepare (by dilution) a 5% lipid emulsion.
CN 101152186 describes the use of the surfactants Solutol S15 or poloxamer 188 in the preparation of injectable progesterone formulations. Whilst use of these surfactants may achieve a high progesterone solubility, intravenous administration of high concentrations of these surfactants is associated with undesirable side-effects including moderate elevation in histamine release, urticaria, and anaphylactic reactions (pruritis, erythema).
One method of increasing the solubility of progesterone in lipid emulsions known in the art is the use of organic solvents. Progesterone is highly soluble in benzoic acid or its derivatives. For example, JP 60-258110 describes the use of benzyl benzoate to increase progesterone solubility in an oil emulsion. However, since benzyl alcohols and benzyl benzoate are commonly toxic and are known to elicit allergies, their inclusion in compositions for parenteral administration is considered a serious danger.
There remains a need, therefore, for physically stable formulations of progestogen suitable for parenteral, particularly intravenous, administration.